Griffin Michelle F, Cook Jessica, Morgan Annah, Boffelli Dario, Downer Mauricio, Spielman Amanda F, Guardino Nicholas J, Guo Jason L, Parker Jennifer B L, Januszyk Michael, Valencia Caleb, Kuhnert Maxwell, Lu John, Zwick Rachel, Wan Derrick C, Klein Ophir D, Longaker Michael T
Department of Surgery, Division of Plastic and Reconstructive Surgery, Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, School of Medicine, Stanford, CA 94305, USA.
Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
Sci Transl Med. 2025 Jul 2;17(805):eadk2101. doi: 10.1126/scitranslmed.adk2101.
Rapid and scarless wound repair is a hallmark of the oral mucosa, yet the cellular and molecular mechanisms that enable this regeneration remain unclear. By comparing populations of murine oral mucosal fibroblasts (OMFs) and facial skin fibroblasts (FSFs), we have identified mechanisms that facilitate regeneration over fibrosis. We found that OMFs used growth arrest specific-6 (GAS6)-angiotoxin receptor-like (AXL) signaling to suppress fibrosis-related mechanosignaling through focal adhesion kinase (FAK) in vitro. Inhibition or knockdown of AXL in the murine oral mucosa resulted in fibrotic wounds and increased activation of FAK. Stimulation of AXL by exogenous GAS6 in the murine facial skin yielded wounds that healed regeneratively as assessed by collagen deposition and organization. Rare human oral scars that resulted from repetitive injury showed decreased expression of GAS6 and AXL and increased FAK. Activating AXL by exogenous GAS6 in repetitively injured mouse oral tissue resulted in better wound healing outcomes and reduced scarring. Altogether, we show that AXL signaling is necessary for murine regenerative wound healing in the oral mucosa and sufficient to limit facial skin fibrosis.
快速且无瘢痕的伤口修复是口腔黏膜的一个标志，然而实现这种再生的细胞和分子机制仍不清楚。通过比较小鼠口腔黏膜成纤维细胞（OMF）和面部皮肤成纤维细胞（FSF）群体，我们确定了促进再生而非纤维化的机制。我们发现，在体外，OMF利用生长停滞特异性蛋白6（GAS6）-血管生成素受体样蛋白（AXL）信号通路，通过粘着斑激酶（FAK）抑制与纤维化相关的机械信号传导。在小鼠口腔黏膜中抑制或敲低AXL会导致纤维化伤口，并增加FAK的激活。在小鼠面部皮肤中，外源性GAS6刺激AXL，根据胶原蛋白沉积和排列评估，产生的伤口以再生方式愈合。因重复性损伤导致的罕见人类口腔瘢痕显示GAS6和AXL表达降低，FAK增加。在外源性GAS6激活重复性损伤的小鼠口腔组织中的AXL会带来更好的伤口愈合结果并减少瘢痕形成。总之，我们表明AXL信号通路对于小鼠口腔黏膜再生性伤口愈合是必需的，并且足以限制面部皮肤纤维化。
